A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors.

Abstract

PURPOSE:

This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors.

PATIENTS AND METHODS:

Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m(2). Pharmacokinetic studies were performed in patients at all dose levels.

RESULT:

Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m(2). One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m(2), and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m(2). Six patients were treated at the 18 mg/m(2) dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t(1/2)) for TTI-237 was 25-29 h, and the mean area under the concentration time curve at 31.5 mg/m(2) was 2,768 ng•h/mL.

CONCLUSION:

A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m(2) may be a tolerable dose of TTI-237.

• Authors: Andrea Wang-Gillam, Susanne M Arnold, Ronald M Bukowski, Mace L Rothenberg, Wendy Cooper, Kenneth K Wang, Eric Gauthier, A Craig Lockhart
• Journal: Investigational new drugs (Invest New Drugs) Vol. 30 Issue 1 Pg. 266-72 (Feb 2012) ISSN: 1573-0646 [Electronic] United States
• PMID: 20697774 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Hydrocarbons, Halogenated
• Triazoles
• Tubulin Modulators
• cevipabulin

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Area Under Curve
• Drug Administration Schedule
• Early Termination of Clinical Trials
• Female
• Half-Life
• Humans
• Hydrocarbons, Halogenated (administration & dosage)
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Treatment Outcome
• Triazoles (administration & dosage)
• Tubulin Modulators (administration & dosage, adverse effects, pharmacokinetics)